Class II MHC molecules primarily bind exogenously derived peptide antigens, producing a complex ligand that can be bound to antigen receptors on CD4+ T lymphocytes. The selectivity of class II molecules for exogenously derived antigen is, in large part, influenced by the chaperone-like effects of the invariant chain (I-i) binding to the alpha- beta complex. Unlike most other integral membrane cell surface proteins, class II molecules do not normally traffic to the plasma membrane via the conventional default or bulk flow (Golgi->plasma membrane) transport route. I-i association with alpha-beta not only targets the class II molecule to the endosomal compartment containing exogenously derived antigen, but also functionally inhibits alpha-beta binding to antigenic peptides during intracellular transport to the endocytic vesicles. Experiments outlined in this grant proposal will characterize potential class II subunit assembly as well as mechanisms regulating intracellular trafficking of class II component polypeptides in murine B lymphoma cells. The experimental approach will be facilitated by inclusion of studies involving A-k expression mutants which have been demonstrated to exhibit unique defects in intracellular transport. Biochemical characterization of these class II mutants provides evidence that the degradative pathways that exist in the endoplasmic reticulum/cis-Golgi and post-Golgi vesicles selectively recognize different types of class Il structural alterations. Characterization of the recognition events that differentially regulate class II transport will enhance our understanding of the intracellular events encountered by this functionally important transport process.
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